Autoimmune mechanisms

Self-Tolerance - Friend or Foe?

• Definition: The immune system's ability to distinguish self from non-self, preventing attacks on its own tissues. Failure leads to autoimmunity.

• Central Tolerance: Occurs in primary lymphoid organs.

  • T-Cells (Thymus): Negative selection eliminates self-reactive T-cells. The AIRE gene is crucial for expressing tissue-specific antigens.
  • B-Cells (Bone Marrow): Receptor editing or apoptosis of self-reactive B-cells.

• Peripheral Tolerance: A backup system for escaped self-reactive lymphocytes.

  • Anergy: Functional inactivation without cell death.
  • Suppression: By regulatory T-cells (Tregs) expressing FOXP3.
  • Activation-Induced Cell Death (AICD): Fas-FasL pathway.

⭐ Mutations in the AIRE gene cause Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy (APECED), also known as APS-1.

Tolerance Breakdown - The System Glitches

• Central Tolerance Failure: Defective negative selection in primary lymphoid organs.

  • AIRE gene mutations → Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy (APECED).

• Peripheral Tolerance Failure: Mature lymphocytes misbehave in secondary tissues.

  • T-Regulatory Cell Defects: FOXP3 mutations → IPEX syndrome (Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked).
  • Molecular Mimicry: Foreign antigen resembles self-antigen. E.g., Rheumatic fever post-Strep infection.
  • Epitope Spreading: Immune response broadens from initial to other self-antigens.
  • Cryptic Antigens: Self-antigens, previously hidden, are exposed by tissue damage or inflammation.

⭐ HLA Association: Many autoimmune diseases are linked to specific HLA subtypes, like HLA-B27 with ankylosing spondylitis.

Damage Mechanisms - Friendly Fire Frenzy

• Type II: Antibody-Mediated (Cytotoxic)

  • IgG/IgM bind to self-antigens on cell surfaces or in the extracellular matrix.
  • Triggers destruction via:
    • Opsonization: Coating for phagocytosis.
    • Complement Activation: Leads to MAC formation & cell lysis.
    • ADCC: NK cells kill antibody-coated targets.

• Type III: Immune Complex-Mediated

  • Antigen-antibody complexes form and deposit in tissues (e.g., vessels, kidneys, joints).
  • Activates complement (C3a, C5a), attracting neutrophils that release damaging enzymes.

• Type IV: T-Cell-Mediated

  • CD4+ T-cells: Secrete cytokines (e.g., IFN-γ) that activate macrophages, leading to chronic inflammation and tissue injury.
  • CD8+ T-cells: Directly kill host cells expressing self-antigens.

⭐ Receptor-Blocking/Stimulating Antibodies: A key Type II variant where antibodies don't cause cell death but alter function. E.g., anti-AChR in Myasthenia Gravis (blocks) or anti-TSHR in Graves' disease (stimulates).

High-Yield Points - ⚡ Biggest Takeaways

• Autoimmunity represents a loss of self-tolerance, leading the immune system to attack host tissues.
• Genetic susceptibility is strongly linked to specific HLA subtypes (e.g., HLA-B27, HLA-DR3/DR4).
• Environmental factors, like infections or UV light, often trigger disease in predisposed individuals.
• Key mechanisms include molecular mimicry, where microbial antigens resemble self-antigens.
• Failure of peripheral tolerance, involving dysfunctional T-regulatory (Treg) cells, is a central defect.
• Tissue damage is mediated by Type II, III, and IV hypersensitivity reactions.